**6. Carotid sinus baroreceptor**

The significance of the ability of the carotid sinus baroreceptor to sense and regulate blood pressure has been known since Hering's publications in 1927. [164]. Later, in1930, Heymans unequivocally demonstrated the chemoreceptor activity of the carotid (or glomus) bodies. [165] However, there have been few human necropsies and therefore, evidence relies on case patients with damage to the carotid sinus and glomus following surgery, radiotherapy and carotid endarterectomy. [166,167] Therefore, little information is available on the morphology of barochemoreceptor structures in disease. [168]

All these findings were highly correlated with high blood pressure and an increase in plasmi‐ nogen activator inhibitor 1 (PAI-1) and transforming growth factor beta-1 (TGF-β-1) deposits in the carotid glomus and autonomic ganglia. Additionally, SHRs presented a higher wall to lumen arteriole ratio in small periglomic vessels, a higher number of S100 protein-positive cells (sustentacular or type 2 cells) and a decreased number of type 1 cells in the carotid glomus. Interestingly, extracellular matrix expansion was highly correlated with the blood pressure level. Because of this, these structures must be considered as target organs in the model of

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Our group carried out an investigation in which the objective was to morphometrically characterize the alterations of the carotid barochemoreceptor structures and their supplying arteries in patients who died from stroke with complicated versus noncomplicated internal carotid atheromatosis. [179] For this purpose, samples consisting of bilateral or unilateral carotid segments were obtained at autopsy from 23 elderly patients who died from ischemic neurological disorders. Transient ischemic attacks preceding their strokes, with extensive

Patients were also divided arbitrarily by age. Group 1 was older than 80 years, Group 2 was 65 to 80 years and Group 3 was younger than 65 years of age. The carotid bifurcation and the first 10 mm to 15 mm of the internal carotid artery were involved in all cases by atherosclerotic lesions. Large lipid cores with a fibrous cap and a band of fibrous tissue of variable thickness separating the plaque from the extensively damaged media were observed in all plaques. In one-third of cases, extensive calcified deposits were also found. The collagen border was frequently vascularized. In most cases, extensive chronic inflammatory infiltrates were observed, consisting of macrophages and minor numbers of lymphocytes as well as extensive neoangiogenesis and calcified deposits. Complicated plaques presented with mononuclear infiltrates in the periphery, shoulders and bases in two-thirds of the cases. In contrast, only

The carotid glomus was located in the carotid fork, measuring approximately 3 mm X 1.5 mm, and formed by lobules compactly arranged, separated by connective tissue [177,180-182] (Figure 21). The functional units consisted of numerous small groups of cells arranged in clusters. They were grouped to form lobules organized as compact nests that were embedded in a fibrous stroma through which numerous nerve fibrils and small blood vessels were observed (Figure 22). Parenchymal cells consisted of two types: the 'chief cells' (epithelioid or type 1 cells), which were large cells with a round nucleus and a large amount of cytoplasm containing vesicles and granules stained by the Grimelius silver reaction; and elongated cells, known as 'sustentacular cells' or type 2 cells. Chief cells were arranged in the centre and sustentacular cells at the periphery. [177] Complex arrangements of afferent nerves and postganglionic sympathetic nerves, as well as autonomic ganglion cells, were found sur‐ rounding the lobules. [181] The carotid glomus showed moderate atrophy and fibrosis to

Plaques were pathologically characterized) into seven categories (see page 3). [18]

one-third of noncomplicated plaques had inflammatory infiltrates (P<0.0001).

severe atrophy with extensive fibrosis (cirrhotic appearance) (Figure 23).

systemic hypertension. [178]

cerebral damage precipitated their deaths.

The baroreflex is very important for the maintenance of arterial pressure, particularly during orthostatic stress. Chemoreflexes play an important role in maintaining blood gas homeostasis. [169] Thus, barochemoreflex failure is a disabling and potentially life-threatening condition. Data on the long-term effect of human bilateral carotid sinus denervation on arterial blood pressure are limited and controversial. [166,170-173]

In patients submitted to bilateral tumoral carotid glomus resection it was found a long-term effect on the level, variability and rapid reflex control of arterial pressure included increased daytime and nighttime blood pressure variability, unopposed sympathetic activation in response to physical and mental stress, and the elimination of orthostatic hypotension and normocapnic hypoxic drive as a result of peripheral chemoreflex failure. [174] Barochemore‐ ceptors are compromised in diseases such as diabetic autonomic neuropathy, Guillain-Barré syndrome, arterial hypertension and heart failure. [175] Fatal complications in most stroke patients likely result from baroreceptor malfunction. [175]

The available experimental and clinical evidence suggests that a pattern of chronic intermittent hypoxia, with short episodes of hypoxia followed by normoxia, selectively enhances the chemosensory and ventilatory responses of the carotid body to hypoxia, suggesting this sensor has an essential role in the enhanced ventilatory and cardiovascular responses observed in animals and obstructive sleep apnea patients. [176]

In a previous study we found a strong involvement of the chemoreceptor structures and corresponding supplying arterioles in a selected group of elderly patients who had died from cerebral vascular disorders with critical carotid artery lesions. [177] Despite the accepted dogma that the amount of connective tissue separating the glomic lobules increases with age, [166] the significant fibrotic involvement and the unquestionable reduction in the vascularity, could not merely be explained by the aging process. However, a possible limitation to the interpretation of those results was the superposition of arterial hypertension, atherosclerosis and aging in the patients.

Due to these facts, and to characterize the potential damage of the carotid glomus related to hemodynamic stress alone, we performed experiments using spontaneously hypertensive rats (SHRs), an animal model with arterial hypertension, in which other factors such as dyslipide‐ mia, high blood sugar or aging were absent. In SHRs, we found a significant increase in extracellular matrix expansion in the carotid glomus and autonomic nerves, along with a decreased number of neurons in autonomic ganglia compared with normotensive controls. All these findings were highly correlated with high blood pressure and an increase in plasmi‐ nogen activator inhibitor 1 (PAI-1) and transforming growth factor beta-1 (TGF-β-1) deposits in the carotid glomus and autonomic ganglia. Additionally, SHRs presented a higher wall to lumen arteriole ratio in small periglomic vessels, a higher number of S100 protein-positive cells (sustentacular or type 2 cells) and a decreased number of type 1 cells in the carotid glomus. Interestingly, extracellular matrix expansion was highly correlated with the blood pressure level. Because of this, these structures must be considered as target organs in the model of systemic hypertension. [178]

**6. Carotid sinus baroreceptor**

60 Carotid Artery Disease - From Bench to Bedside and Beyond

of barochemoreceptor structures in disease. [168]

pressure are limited and controversial. [166,170-173]

patients likely result from baroreceptor malfunction. [175]

animals and obstructive sleep apnea patients. [176]

and aging in the patients.

The significance of the ability of the carotid sinus baroreceptor to sense and regulate blood pressure has been known since Hering's publications in 1927. [164]. Later, in1930, Heymans unequivocally demonstrated the chemoreceptor activity of the carotid (or glomus) bodies. [165] However, there have been few human necropsies and therefore, evidence relies on case patients with damage to the carotid sinus and glomus following surgery, radiotherapy and carotid endarterectomy. [166,167] Therefore, little information is available on the morphology

The baroreflex is very important for the maintenance of arterial pressure, particularly during orthostatic stress. Chemoreflexes play an important role in maintaining blood gas homeostasis. [169] Thus, barochemoreflex failure is a disabling and potentially life-threatening condition. Data on the long-term effect of human bilateral carotid sinus denervation on arterial blood

In patients submitted to bilateral tumoral carotid glomus resection it was found a long-term effect on the level, variability and rapid reflex control of arterial pressure included increased daytime and nighttime blood pressure variability, unopposed sympathetic activation in response to physical and mental stress, and the elimination of orthostatic hypotension and normocapnic hypoxic drive as a result of peripheral chemoreflex failure. [174] Barochemore‐ ceptors are compromised in diseases such as diabetic autonomic neuropathy, Guillain-Barré syndrome, arterial hypertension and heart failure. [175] Fatal complications in most stroke

The available experimental and clinical evidence suggests that a pattern of chronic intermittent hypoxia, with short episodes of hypoxia followed by normoxia, selectively enhances the chemosensory and ventilatory responses of the carotid body to hypoxia, suggesting this sensor has an essential role in the enhanced ventilatory and cardiovascular responses observed in

In a previous study we found a strong involvement of the chemoreceptor structures and corresponding supplying arterioles in a selected group of elderly patients who had died from cerebral vascular disorders with critical carotid artery lesions. [177] Despite the accepted dogma that the amount of connective tissue separating the glomic lobules increases with age, [166] the significant fibrotic involvement and the unquestionable reduction in the vascularity, could not merely be explained by the aging process. However, a possible limitation to the interpretation of those results was the superposition of arterial hypertension, atherosclerosis

Due to these facts, and to characterize the potential damage of the carotid glomus related to hemodynamic stress alone, we performed experiments using spontaneously hypertensive rats (SHRs), an animal model with arterial hypertension, in which other factors such as dyslipide‐ mia, high blood sugar or aging were absent. In SHRs, we found a significant increase in extracellular matrix expansion in the carotid glomus and autonomic nerves, along with a decreased number of neurons in autonomic ganglia compared with normotensive controls. Our group carried out an investigation in which the objective was to morphometrically characterize the alterations of the carotid barochemoreceptor structures and their supplying arteries in patients who died from stroke with complicated versus noncomplicated internal carotid atheromatosis. [179] For this purpose, samples consisting of bilateral or unilateral carotid segments were obtained at autopsy from 23 elderly patients who died from ischemic neurological disorders. Transient ischemic attacks preceding their strokes, with extensive cerebral damage precipitated their deaths.

Plaques were pathologically characterized) into seven categories (see page 3). [18]

Patients were also divided arbitrarily by age. Group 1 was older than 80 years, Group 2 was 65 to 80 years and Group 3 was younger than 65 years of age. The carotid bifurcation and the first 10 mm to 15 mm of the internal carotid artery were involved in all cases by atherosclerotic lesions. Large lipid cores with a fibrous cap and a band of fibrous tissue of variable thickness separating the plaque from the extensively damaged media were observed in all plaques. In one-third of cases, extensive calcified deposits were also found. The collagen border was frequently vascularized. In most cases, extensive chronic inflammatory infiltrates were observed, consisting of macrophages and minor numbers of lymphocytes as well as extensive neoangiogenesis and calcified deposits. Complicated plaques presented with mononuclear infiltrates in the periphery, shoulders and bases in two-thirds of the cases. In contrast, only one-third of noncomplicated plaques had inflammatory infiltrates (P<0.0001).

The carotid glomus was located in the carotid fork, measuring approximately 3 mm X 1.5 mm, and formed by lobules compactly arranged, separated by connective tissue [177,180-182] (Figure 21). The functional units consisted of numerous small groups of cells arranged in clusters. They were grouped to form lobules organized as compact nests that were embedded in a fibrous stroma through which numerous nerve fibrils and small blood vessels were observed (Figure 22). Parenchymal cells consisted of two types: the 'chief cells' (epithelioid or type 1 cells), which were large cells with a round nucleus and a large amount of cytoplasm containing vesicles and granules stained by the Grimelius silver reaction; and elongated cells, known as 'sustentacular cells' or type 2 cells. Chief cells were arranged in the centre and sustentacular cells at the periphery. [177] Complex arrangements of afferent nerves and postganglionic sympathetic nerves, as well as autonomic ganglion cells, were found sur‐ rounding the lobules. [181] The carotid glomus showed moderate atrophy and fibrosis to severe atrophy with extensive fibrosis (cirrhotic appearance) (Figure 23).

**Figure 23.** Carotid glomus. A Marked decrease in cells and moderate fibrosis. Typical rounded chief cells are shown in the centre of the section (arrowhead).Hematoxylin and eosin stain; ×400 objective lens. B Severe atrophy and, in some areas, absence of acinar structures with replacement by dense connective tissue with a so-called 'cirrhotic' appearance

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There was a loss of the characteristic chief cells (more than 50%) and loss of their argyrophilic Grimelius-staining granules, suggesting a decrease in their catecholamine content. Fibrosis and glomic cell loss was assessed as 2.6±0.5. A focal reduction of glomus vascularization (more than 50%) was also observed in the areas of atrophy and fibrosis when capillaries were stained with anti-CD34, which was assessed as 2.76±0.6 (Figure 24) In a few cases, it was possible to observe autonomic ganglia showing moderate fibrosis, mild-to-moderate neuronal damage and lipofuscin deposits (Figure 25). Interestingly, the arterioles to the glomus showed severe fibrointimal proliferation and disruption of the internal elastic lamina, marked thickening of the media and luminal narrowing. Luminal thrombi were also observed, as well as focal areas of medial homogenization (Figure 26). At the outer media of the carotid sinus, corresponding to the deeper layers of the plaques, it was possible to identify damaged nerve endings that reacted specifically with S100 protein. No differences were found among groups for glomus area, number of type 1 cells, number of type 2 cells or the wall to lumen arteriole ratio. Also, no statistical differences could be demonstrated when complicated (intraplaque hemorrhage and/or rupture and/or thrombosis) and noncomplicated plaques were compared or when comparing age groups 1, 2 and 3. No correlation between morphometric data and age was found. Patients with stenosis of the extracranial carotid arteries constitute a multimorbid population that frequently shows several vascular risk factors, including hypertension and diabetes. Our study [179] demonstrated that, in patients who died from cerebral vascular disorders with critical carotid artery lesions, a strong involvement of the chemoreceptor

Accordingly, at the outer media of the carotid sinus, corresponding to the deeper fibrocalcified layers of the plaques and in periglomic areas, damaged nerve endings were observed as well as fibrotic autonomic ganglia. Therefore, a strong involvement of the baro-(carotid sinus) and chemoreceptor (carotid body or glomus) structures and their corresponding nerves and arterioles was observed in the group of elderly patients. These lesions were independent of patient age, as well as the presence of a complicated carotid plaque. Despite the observation that the connective tissue separating the glomic lobules increases with age, [166] the marked fibrotic involvement and the clear decrease in its rich vascularity, shown by the CD34 immu‐ nophenotyping, cannot be explained only in terms of aging. Several studies have found the

(asterisk). Hematoxylin and eosin stain; ×100 objective lens

structures and their supplying arterioles was found.

**Figure 21.** Whole specimen of a frontally cut carotid segment. The arrow points to the glomus located in the intersti‐ tial tissue between the internal and external carotid arteries and its corresponding nerves. Multiple nonstenotic fibroli‐ pidic and fibrotic plaques are observed along the carotid axis.Also an intraplaque hemorrhage is shown (asterisk)Hematoxylin and eosin stain; ×20 objective lens. 1 Common carotid artery;2 External carotid artery showing an atheroma inside (P)

**Figure 22.** Carotid glomus showing almost normal structure and vascularization.Veins are dilated (arrow) and there is a mild increase in interstitial fibrosis (asterisk). Hematoxylin and eosin stain; ×100 objective lens

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**Figure 23.** Carotid glomus. A Marked decrease in cells and moderate fibrosis. Typical rounded chief cells are shown in the centre of the section (arrowhead).Hematoxylin and eosin stain; ×400 objective lens. B Severe atrophy and, in some areas, absence of acinar structures with replacement by dense connective tissue with a so-called 'cirrhotic' appearance (asterisk). Hematoxylin and eosin stain; ×100 objective lens

There was a loss of the characteristic chief cells (more than 50%) and loss of their argyrophilic Grimelius-staining granules, suggesting a decrease in their catecholamine content. Fibrosis and glomic cell loss was assessed as 2.6±0.5. A focal reduction of glomus vascularization (more than 50%) was also observed in the areas of atrophy and fibrosis when capillaries were stained with anti-CD34, which was assessed as 2.76±0.6 (Figure 24) In a few cases, it was possible to observe autonomic ganglia showing moderate fibrosis, mild-to-moderate neuronal damage and lipofuscin deposits (Figure 25). Interestingly, the arterioles to the glomus showed severe fibrointimal proliferation and disruption of the internal elastic lamina, marked thickening of the media and luminal narrowing. Luminal thrombi were also observed, as well as focal areas of medial homogenization (Figure 26). At the outer media of the carotid sinus, corresponding to the deeper layers of the plaques, it was possible to identify damaged nerve endings that reacted specifically with S100 protein. No differences were found among groups for glomus area, number of type 1 cells, number of type 2 cells or the wall to lumen arteriole ratio. Also, no statistical differences could be demonstrated when complicated (intraplaque hemorrhage and/or rupture and/or thrombosis) and noncomplicated plaques were compared or when comparing age groups 1, 2 and 3. No correlation between morphometric data and age was found. Patients with stenosis of the extracranial carotid arteries constitute a multimorbid population that frequently shows several vascular risk factors, including hypertension and diabetes. Our study [179] demonstrated that, in patients who died from cerebral vascular disorders with critical carotid artery lesions, a strong involvement of the chemoreceptor structures and their supplying arterioles was found.

**Figure 21.** Whole specimen of a frontally cut carotid segment. The arrow points to the glomus located in the intersti‐ tial tissue between the internal and external carotid arteries and its corresponding nerves. Multiple nonstenotic fibroli‐ pidic and fibrotic plaques are observed along the carotid axis.Also an intraplaque hemorrhage is shown (asterisk)Hematoxylin and eosin stain; ×20 objective lens. 1 Common carotid artery;2 External carotid artery showing

**Figure 22.** Carotid glomus showing almost normal structure and vascularization.Veins are dilated (arrow) and there is

a mild increase in interstitial fibrosis (asterisk). Hematoxylin and eosin stain; ×100 objective lens

an atheroma inside (P)

62 Carotid Artery Disease - From Bench to Bedside and Beyond

Accordingly, at the outer media of the carotid sinus, corresponding to the deeper fibrocalcified layers of the plaques and in periglomic areas, damaged nerve endings were observed as well as fibrotic autonomic ganglia. Therefore, a strong involvement of the baro-(carotid sinus) and chemoreceptor (carotid body or glomus) structures and their corresponding nerves and arterioles was observed in the group of elderly patients. These lesions were independent of patient age, as well as the presence of a complicated carotid plaque. Despite the observation that the connective tissue separating the glomic lobules increases with age, [166] the marked fibrotic involvement and the clear decrease in its rich vascularity, shown by the CD34 immu‐ nophenotyping, cannot be explained only in terms of aging. Several studies have found the grade of fibrosis to be dependent on age, [183] while others have demonstrated considerable differences, not only within comparable age groups but, in a few cases, between the right and left sides. [184]

**Figure 24.** A :Acinar structure belonging to a carotid glomus showing a moderate-to-severe decrease in the number of chief cells, and loss of argyrophilic intracellular granules (shown in black). Grimelius stain; ×200 objective lens. B: Carotid glomus. A focal absence and global decrease of vascularization is shown in the areas of acinar atrophy and fibrosis. anti-CD34 stain; ×100 objective lens

age. [185] However, in the rat, aging of the cardiovascular system may not be associated with the attenuation of the baroreflex function. [184] Accordingly, the carotid baroreceptor reflex is well maintained in both young and old dogs, suggesting a lack of morphological involve‐ ment. [186] Nevertheless, the attenuation of the baroreflex is far less pronounced in patients

**Figure 26.** A::Glomic arteriole showing marked intimal fibrosis with moderate thickening of the media and focal areas of medial homogenization, and severe adventitial fibrosis. Hematoxylin and eosin stain; ×100 objective lens. B: Glomic arteriole with marked fibrointimal proliferation and thickening of the wall with luminal narrowing. Azan stain; ×100 objective lens. C: Small artery supplying the glomus. Marked fibrointimal fibrosis with reduction of the lumen and me‐

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Therefore, it is possible that the age-related baroreflex attenuation observed in humans may not be due to aging *per se* but may instead reflect atherosclerotic and/or hypertensive processes. [188-189] There are few data concerning the dependency of the various kinds of chemoreflex sensitivity on age in healthy human subjects. A study [185] however, showed no significant correlation between chemoreflex sensitivity and age in patients with multiple organ dysfunc‐ tion syndrome. The authors hypothesized that this lack of correlation can be interpreted as a confirmation that the effect of the disease prevails over aging in pathological conditions.

Early studies [187-189] speculated that a high systemic arterial pressure may deactivate the baroreceptor function by damaging the nerve endings in the arterial wall. An alternative explanation was issued by Heath and Smith, [190] who suggested that an increased stiffness of the arterial wall would splint the baroreceptor endings, reducing their sensitivity to changes in arterial pressure instead. These authors pointed out that, to some extent, atherosclerosis must depend on the orientation of the receptors in the arterial wall. If they are pulled circum‐ ferentially, an increased rigidity of the arterial wall should lead to a decreased baroreceptor response. In contrast, if the structure is compressed outwards from within, an increased

Baroreflex is aroused by changes in blood pressure that are collected by autonomic nerve 'sensors' that are distributed in the arterial tree and convey the stimuli elicited by mean pressure, rate of change in pressure (dP/dt), pulse pressure and heart rate. These mechanore‐ ceptors, typically gathered in the outer tunica media of the carotid sinus, are found as nerve terminals and, occasionally, with the features of drumstick swellings. The smooth muscle layer is thinner there to allow for an increased vessel compliance favouring an enhanced mechanical

in whom the possible effects of disease counteract the age effects. [187]

dial fibrosis. Azan stain; ×100 objective lens

rigidity of the vessel wall may not have such an effect. [191]

stimulation. [192]

**Figure 25.** Autonomic ganglia showing moderate fibrosis and mild-to moderate neuronal damage with intracytoplas‐ mic lipofuscin deposits (arrowhead).Hematoxylin and eosin stain; ×200 objective lens

On the other hand, examination of surgical specimens removed from patients older than 60 years of age showed that the organ almost had a 'cirrhotic' appearance. [181] This suggests an arteriolar involvement leading to fibrosis by a chronic hypoxic mechanism. Most of the autonomic parameters, including heart rate variability and baroreflex sensitivity, decline with Carotid Artery – Pathology, Plaque Structure – Relationship between Histological Assessment, Color Doppler... http://dx.doi.org/10.5772/57157 65

grade of fibrosis to be dependent on age, [183] while others have demonstrated considerable differences, not only within comparable age groups but, in a few cases, between the right and

**Figure 24.** A :Acinar structure belonging to a carotid glomus showing a moderate-to-severe decrease in the number of chief cells, and loss of argyrophilic intracellular granules (shown in black). Grimelius stain; ×200 objective lens. B: Carotid glomus. A focal absence and global decrease of vascularization is shown in the areas of acinar atrophy and

**Figure 25.** Autonomic ganglia showing moderate fibrosis and mild-to moderate neuronal damage with intracytoplas‐

On the other hand, examination of surgical specimens removed from patients older than 60 years of age showed that the organ almost had a 'cirrhotic' appearance. [181] This suggests an arteriolar involvement leading to fibrosis by a chronic hypoxic mechanism. Most of the autonomic parameters, including heart rate variability and baroreflex sensitivity, decline with

mic lipofuscin deposits (arrowhead).Hematoxylin and eosin stain; ×200 objective lens

left sides. [184]

64 Carotid Artery Disease - From Bench to Bedside and Beyond

fibrosis. anti-CD34 stain; ×100 objective lens

**Figure 26.** A::Glomic arteriole showing marked intimal fibrosis with moderate thickening of the media and focal areas of medial homogenization, and severe adventitial fibrosis. Hematoxylin and eosin stain; ×100 objective lens. B: Glomic arteriole with marked fibrointimal proliferation and thickening of the wall with luminal narrowing. Azan stain; ×100 objective lens. C: Small artery supplying the glomus. Marked fibrointimal fibrosis with reduction of the lumen and me‐ dial fibrosis. Azan stain; ×100 objective lens

age. [185] However, in the rat, aging of the cardiovascular system may not be associated with the attenuation of the baroreflex function. [184] Accordingly, the carotid baroreceptor reflex is well maintained in both young and old dogs, suggesting a lack of morphological involve‐ ment. [186] Nevertheless, the attenuation of the baroreflex is far less pronounced in patients in whom the possible effects of disease counteract the age effects. [187]

Therefore, it is possible that the age-related baroreflex attenuation observed in humans may not be due to aging *per se* but may instead reflect atherosclerotic and/or hypertensive processes. [188-189] There are few data concerning the dependency of the various kinds of chemoreflex sensitivity on age in healthy human subjects. A study [185] however, showed no significant correlation between chemoreflex sensitivity and age in patients with multiple organ dysfunc‐ tion syndrome. The authors hypothesized that this lack of correlation can be interpreted as a confirmation that the effect of the disease prevails over aging in pathological conditions.

Early studies [187-189] speculated that a high systemic arterial pressure may deactivate the baroreceptor function by damaging the nerve endings in the arterial wall. An alternative explanation was issued by Heath and Smith, [190] who suggested that an increased stiffness of the arterial wall would splint the baroreceptor endings, reducing their sensitivity to changes in arterial pressure instead. These authors pointed out that, to some extent, atherosclerosis must depend on the orientation of the receptors in the arterial wall. If they are pulled circum‐ ferentially, an increased rigidity of the arterial wall should lead to a decreased baroreceptor response. In contrast, if the structure is compressed outwards from within, an increased rigidity of the vessel wall may not have such an effect. [191]

Baroreflex is aroused by changes in blood pressure that are collected by autonomic nerve 'sensors' that are distributed in the arterial tree and convey the stimuli elicited by mean pressure, rate of change in pressure (dP/dt), pulse pressure and heart rate. These mechanore‐ ceptors, typically gathered in the outer tunica media of the carotid sinus, are found as nerve terminals and, occasionally, with the features of drumstick swellings. The smooth muscle layer is thinner there to allow for an increased vessel compliance favouring an enhanced mechanical stimulation. [192]

Adjustment of the respiration rate in response to changes in levels of oxygen, carbon dioxide and hydrogen ions in body fluids are mediated by a complex interplay between central and peripheral chemoreceptors. The peripheral arterial chemoreceptors, located in the carotid and aortic glomus, are responsible for the immediate ventilatory and arterial pressure increments during acute hypoxia. [165] Type 1 cells in the carotid and aortic glomus release neurotransmitters in response to hypoxia, causing depolarization of nearby afferent nerve endings. [191,192]

not be due to aging per se, but it may reflect atherosclerotic and/or hypertensive processes.

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Carotid barochemoreceptors are of utmost importance in the rapid adjustment of circulation and ventilation; the different degrees of involvement of these structures may explain various clinical responses. [196] These may encompass chronic hypertension, isolated systolic hyper‐ tension, blood pressure lability, postural lightheadedness and periodic orthostatic hypoten‐ sion. [196] Elderly hypertensive patients with these relatively common conditions could be

Cooper et al [197] reported that the effect of both peripheral and central chemoreceptors on baroreflex function may contribute to promoting hypertension in patients with obstructive sleep apnea.Accordingly, Kario et al [196] investigated the clinical significance and mechanism of orthostatic blood pressure dysregulation in elderly hypertensive patients. They found that silent cerebrovascular disease is advanced in elderly patients with orthostatic hyperten‐ sion.Elderly hypertensive patients with orthostatic hypertension or orthostatic hypotension may have an increased risk for developing cerebrovascular disease. In conclusion Severe carotid chemoreceptor damage exists in elderly patients who died from stroke and suffered from carotid atheromatosis, independently from aging and plaque type. The damage is plausibly related to a marked narrowing of their supplying arterioles as a consequence of hemodynamic (hypertension) and/or metabolic (diabetes, dyslipidemia) disturbances.

A high density of angiotensin II receptors was observed in the rat carotid body by in vitro autoradiography employing 125I- [SarÁ,IleÌ]-angiotensin II as radioligand. Displacement

As written above, the renin-angiotensin system has been shown to be responsible for ageing and hypertension which are the major risk factors for the development of cardiovascular and renal diseases.[197,199-202] We conducted an investigation [203] in which the the aim was to compare the effects of losartan, an angiotensin II type-1 receptor blocker, on systolic blood pressure, (SBP), and histopathologycal changes in the carotid body and autonomic lymphs in 14 spontaneously normotensive rats (WKY) They were divided into two groups, one of them treated with Losartan (n=7) and the other was a control group (n=7) not receving this drug. We also compared to spontaneously hypertensive rats (SHRs). As expected, at the end of the study the rats treated with losartan had a SBP of 105 ± 8.3 mm Hg, significantly less than controls (115 ± 8.1 mm Hg, p = 0.0375).The carotid body was found in the area fork or carotid bifurcation, formed by lobes compact traversed separated by connective tissue by numerous small blood vessels and nerve fibers blood (Figure 1). Parenchyma was formed by two cell types: primary cells or type I, large round nuclei and cells Hold or type II, elongated and located peripherally of the first (Figure 2). Lobes comprise the functional units of the structure they were best preserved in the group treated with losartan (Figure 3, A). Also, fibrous stroma was much more apparent in the control group, where the gap was increased with cell replacement and decreased in number (Figure 4, A). Clearly losartan treated rats showed glomus area more, a smaller thickness wall in the arterioles and a light periglómicas higher compared with the control group (Figures 3 and 4, A, B, C). All this made that the losartan group had a wall / lumen ratio significantly lower than controls in these vessels. These findings strongly suggest

studies demonstrated that the receptors were of the AT1 subtype. [198]

[177,188,189]

considered as a high-risk stroke group. [19,177]

Unquestionably, permanent high blood pressure causes a deleterious effect in peripheral nervous structures. However, few studies deal with the findings reported in our papers [18,177,178] regarding the deleterious effect of arterial hypertension on carotid glomus and autonomic ganglia.

As said, our studies in SHRs has demonstrated a strong correlation between arterial hyper‐ tension and the development of lesions in the carotid glomus and autonomic ganglia charac‐ terized by extracellular matrix expansion, as well as a reduction in the number of ganglia neurons. [178]

Because lowering blood pressure is the first step in controlling the deleterious effects of arterial hypertension, we have evaluated the possible differences between the effects of the beta-blocker atenolol (AT) and the ACEI ramipril (RAM) regarding a protective role on these structures, as target organs in SHRs. [193] At the end of the experiment, SHRs receiving AT and SHRs receiving RAM (SHR-RAM) showed a similar control in blood pressure compared with untreated SHRs. However, SHR-RAM presented with a signifi‐ cant reduction in extracellular matrix expansion in the carotid glomus, autonomic gan‐ glia and autonomic nerves. Moreover, the number of neurons was preserved with AT and even more with RAM compared with the untreated SHR group. TGF-β-1 and PAI-1 were increased in the carotid glomus and autonomic ganglia in SHRs and in SHRs receiving AT, whereas SHR-RAM showed a similar expression to the normotensive group (Wistar-Kyoto rats), indicating that RAM, but not AT, provided a significant protective role against structural changes in these structures caused by arterial hypertension in SHRs. This effect seems to be independent of blood pressure reduction. [194]

These structures were well preserved by an ACEI because permanent high blood pressure stimulates extracellular matrix expansion as a result of enhanced TGF-β-1 and PAI-1 produc‐ tion, through a mechanism regulated by the renin-angiotensin-aldosterone system. [193]

Previous studies have shown the existence of a local reninangiotensin-aldosterone system in the carotid glomus. [194] In agreement with this information, ACEIs could prevent fibrosis in barochemoreceptor structures observed in SHR by reducing local angiotensin II production. [194] The clinical importance of these data could be that the baroreflex attenuation in humans might be a consequence of atherosclerotic and/or hypertensive processes. [177,187,188]

Also the relationship between atherosclerosis and baroreflex sensitivity has been well docu‐ mented in animal models. [55,63,194,195] Similar evidence in humans is both limited and indirect. [64] It is possible that the age-related baroreflex attenuation observed in humans may not be due to aging per se, but it may reflect atherosclerotic and/or hypertensive processes. [177,188,189]

Adjustment of the respiration rate in response to changes in levels of oxygen, carbon dioxide and hydrogen ions in body fluids are mediated by a complex interplay between central and peripheral chemoreceptors. The peripheral arterial chemoreceptors, located in the carotid and aortic glomus, are responsible for the immediate ventilatory and arterial pressure increments during acute hypoxia. [165] Type 1 cells in the carotid and aortic glomus release neurotransmitters in response to hypoxia, causing depolarization of nearby

Unquestionably, permanent high blood pressure causes a deleterious effect in peripheral nervous structures. However, few studies deal with the findings reported in our papers [18,177,178] regarding the deleterious effect of arterial hypertension on carotid glomus and

As said, our studies in SHRs has demonstrated a strong correlation between arterial hyper‐ tension and the development of lesions in the carotid glomus and autonomic ganglia charac‐ terized by extracellular matrix expansion, as well as a reduction in the number of ganglia

Because lowering blood pressure is the first step in controlling the deleterious effects of arterial hypertension, we have evaluated the possible differences between the effects of the beta-blocker atenolol (AT) and the ACEI ramipril (RAM) regarding a protective role on these structures, as target organs in SHRs. [193] At the end of the experiment, SHRs receiving AT and SHRs receiving RAM (SHR-RAM) showed a similar control in blood pressure compared with untreated SHRs. However, SHR-RAM presented with a signifi‐ cant reduction in extracellular matrix expansion in the carotid glomus, autonomic gan‐ glia and autonomic nerves. Moreover, the number of neurons was preserved with AT and even more with RAM compared with the untreated SHR group. TGF-β-1 and PAI-1 were increased in the carotid glomus and autonomic ganglia in SHRs and in SHRs receiving AT, whereas SHR-RAM showed a similar expression to the normotensive group (Wistar-Kyoto rats), indicating that RAM, but not AT, provided a significant protective role against structural changes in these structures caused by arterial hypertension in SHRs. This effect

These structures were well preserved by an ACEI because permanent high blood pressure stimulates extracellular matrix expansion as a result of enhanced TGF-β-1 and PAI-1 produc‐ tion, through a mechanism regulated by the renin-angiotensin-aldosterone system. [193]

Previous studies have shown the existence of a local reninangiotensin-aldosterone system in the carotid glomus. [194] In agreement with this information, ACEIs could prevent fibrosis in barochemoreceptor structures observed in SHR by reducing local angiotensin II production. [194] The clinical importance of these data could be that the baroreflex attenuation in humans might be a consequence of atherosclerotic and/or hypertensive processes. [177,187,188]

Also the relationship between atherosclerosis and baroreflex sensitivity has been well docu‐ mented in animal models. [55,63,194,195] Similar evidence in humans is both limited and indirect. [64] It is possible that the age-related baroreflex attenuation observed in humans may

seems to be independent of blood pressure reduction. [194]

afferent nerve endings. [191,192]

66 Carotid Artery Disease - From Bench to Bedside and Beyond

autonomic ganglia.

neurons. [178]

Carotid barochemoreceptors are of utmost importance in the rapid adjustment of circulation and ventilation; the different degrees of involvement of these structures may explain various clinical responses. [196] These may encompass chronic hypertension, isolated systolic hyper‐ tension, blood pressure lability, postural lightheadedness and periodic orthostatic hypoten‐ sion. [196] Elderly hypertensive patients with these relatively common conditions could be considered as a high-risk stroke group. [19,177]

Cooper et al [197] reported that the effect of both peripheral and central chemoreceptors on baroreflex function may contribute to promoting hypertension in patients with obstructive sleep apnea.Accordingly, Kario et al [196] investigated the clinical significance and mechanism of orthostatic blood pressure dysregulation in elderly hypertensive patients. They found that silent cerebrovascular disease is advanced in elderly patients with orthostatic hyperten‐ sion.Elderly hypertensive patients with orthostatic hypertension or orthostatic hypotension may have an increased risk for developing cerebrovascular disease. In conclusion Severe carotid chemoreceptor damage exists in elderly patients who died from stroke and suffered from carotid atheromatosis, independently from aging and plaque type. The damage is plausibly related to a marked narrowing of their supplying arterioles as a consequence of hemodynamic (hypertension) and/or metabolic (diabetes, dyslipidemia) disturbances.

A high density of angiotensin II receptors was observed in the rat carotid body by in vitro autoradiography employing 125I- [SarÁ,IleÌ]-angiotensin II as radioligand. Displacement studies demonstrated that the receptors were of the AT1 subtype. [198]

As written above, the renin-angiotensin system has been shown to be responsible for ageing and hypertension which are the major risk factors for the development of cardiovascular and renal diseases.[197,199-202] We conducted an investigation [203] in which the the aim was to compare the effects of losartan, an angiotensin II type-1 receptor blocker, on systolic blood pressure, (SBP), and histopathologycal changes in the carotid body and autonomic lymphs in 14 spontaneously normotensive rats (WKY) They were divided into two groups, one of them treated with Losartan (n=7) and the other was a control group (n=7) not receving this drug. We also compared to spontaneously hypertensive rats (SHRs). As expected, at the end of the study the rats treated with losartan had a SBP of 105 ± 8.3 mm Hg, significantly less than controls (115 ± 8.1 mm Hg, p = 0.0375).The carotid body was found in the area fork or carotid bifurcation, formed by lobes compact traversed separated by connective tissue by numerous small blood vessels and nerve fibers blood (Figure 1). Parenchyma was formed by two cell types: primary cells or type I, large round nuclei and cells Hold or type II, elongated and located peripherally of the first (Figure 2). Lobes comprise the functional units of the structure they were best preserved in the group treated with losartan (Figure 3, A). Also, fibrous stroma was much more apparent in the control group, where the gap was increased with cell replacement and decreased in number (Figure 4, A). Clearly losartan treated rats showed glomus area more, a smaller thickness wall in the arterioles and a light periglómicas higher compared with the control group (Figures 3 and 4, A, B, C). All this made that the losartan group had a wall / lumen ratio significantly lower than controls in these vessels. These findings strongly suggest atrophy of the structures analyzed. Through the increasing age is mainly linked with decreased arterial blood supply them and that the inhibition of AT1 receptor would a prominent role in the prevention of such alterations.

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In conclusion, a severe carotid chemoreceptor damage does exist in old patients who died from stroke and suffering from carotid atheromatosis. The damage involved the glomic structures and of note, a ''culprit'' narrowing of the arterioles belonging to those structures was also observed. The clinical implications of these findings related to the development and/or worsening of all types of blood pressure and ventilatory disturbances in elderly patients are obvious. Hypertension could play aa very important role in the development of carotid body lesions -Beta blockade or Ramipril or Losartan could prevent morphologic and functional abnormalities
